Application Identifier: 364510 Application Project Title: Advancing KNX100 for the treatment of opioid withdrawal: preclinical efficacy and toxicology, and a phase 1 clinical program. Project Summary/Abstract Kinoxis Therapeutics Pty Ltd is an Australian based company that has licensed intellectual property from the University of Sydney, including several candidates for the treatment of substance use disorders. We have developed a novel small molecule lead, KNX100, which is showing considerable promise in preclinical animal models of a range of substance use disorders, including models of OUD, with particularly impressive efficacy at reducing the severity of opioid withdrawal symptoms in mice. KNX100 was discovered from a phenotypic screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin system. KNX100 has a favorable pharmacokinetic and safety profile in testing thus far. To date, KNX100 has undergone testing for efficacy signals in two rodent and two non-human primate species, with testing taking place across multiple laboratories including National Institute on Drug Abuse (NIDA) commissioned laboratories under the NIDA Medications Development Program. The proposed activity under this funding opportunity is to progress the development of KNX100 in opioid use disorder, with the specific indication being treatment of opioid withdrawal. The overall objective of the project is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and ultimately enable a New Drug Application to the FDA. The company has developed a research plan which entails both a UG3 Phase and a UH3 Phase. For the UG3 Phase, the company plans to complete all the necessary IND enabling studies required for FDA approval to administer KNX100 in a first in man, Phase 1 clinical study. The program includes additional testing of KNX100 in animal models of opioid withdrawal; scale up and manufacture of drug substance and drug product to support both the non-clinical and clinical programs; a toxicology program to generate data to support the Phase 1 study; and the submission of an Investigational New Drug Application to the FDA. Following the successful completion of the UG3 Phase, measured by the milestone of FDA Clearance of an IND Application to a Commence a Phase 1 Study without a clinical hold, the company would then progress into the UH3 Phase by completing a Phase 1 clinical program to establish the safety and tolerability of KNX100 when dosed in humans. The purpose of this NIH/NIDA Funding Opportunity Announcement (RFA-DA-19-002), for which this application is being submitted, is to support the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose. The development of KNX100 offers an opportunity to provide a more efficacious and/or safer alternative to the current only approved medication for opioid withdrawal, lofexidine, and this application will accelerate the development toward this objective.